In recent years there has been a strong interest in the potential effect of migraine disease on other illnesses. Our understanding of the complex pathophysiology of migraine disease that may underlie nonheadache symptoms and syndromes is currently marked by a long list of comorbid disorders. The connection of migraine to other conditions is at various levels of explanation, ranging from some intriguing clinical observations to accepted criteria as a migraine subtype. This is a snapshot of the level of current knowledge of migraine comorbidities and the significance of this information, but the complexity of this subject will be a challenge for a generation of clinicians and scientists.

Some children have visual disturbances that occur in the absence of, or are out of proportion to, their objective ophthalmological findings. These symptoms reflect a wide range of processes that may be benign or a sign of neurological, systemic, or psychiatric disease. This chapter deals with the neuro-ophthalmologic detection of organic and psychogenic disorders that may manifest as transient or unexplained visual loss, along with other episodic visual disturbances that occur in childhood. In these cases, several formidable problems confront the physician who is trying to reach the correct diagnosis. The descriptions of episodic visual disturbances and hallucinations in children are generally less complex in detail than those in the adult population because children have a limited vocabulary and a limited experiential basis of sensory phenomena to draw upon.

Chronic migraine is a debilitating primary headache disorder associated with high personal, familial, and social impact. The diagnosis is made when there are at least 15 headache days monthly including 8 migraine days per month for at least 3 months. The prevalence is 1.4–2.2% in the population. Among individuals diagnosed with chronic migraine, there may be significant variability in headache days with a potential to remit, remain unchanged, or progress to even greater disability. Most chronic migraine progresses from episodic migraine, with several identified risk factors for chronic migraine and migraine progression. The exact mechanism of chronic migraine is unknown but is associated with an increased cortical excitability, central sensitization, alternations in nociceptive signaling, as well as physiological, structural, and functional brain changes. There is evidence for both nonpharmacological and pharmacological treatment options to restore function. The best currently established pharmacologic evidence for the treatment of chronic migraine is onabotulinumtoxinA and topiramate. Behavioral treatments may improve headache symptoms and comorbidities. Emerging data shows potential benefit for neurostimulation, and large well-designed studies are needed. Multicenter randomized placebo-controlled studies of monoclonal antibodies to the calcitonin gene-related peptide, or its receptor, have demonstrated efficacy, tolerability, and safety. Biomarkers are needed to guide prognosis, treatment response, and clinical trials. The concept and management of refractory chronic migraine is discussed, and clinically meaningful endpoints are reviewed.

Some children have visual disturbances that occur in the absence of, or are out of proportion to, their objective ophthalmological findings. These symptoms reflect a wide range of processes that may be benign or a sign of neurological, systemic, or psychiatric disease. This chapter deals with the neuro-ophthalmologic detection of organic and psychogenic disorders that may manifest as transient or unexplained visual loss of the same episodic visual disturbances that occur in childhood, but several formidable problems confront the physician who is trying to reach the correct diagnosis. The descriptions of episodic visual disturbances and hallucinations in children are less complex in detail than those of the adult population because children have limited vocabulary and limited experiential basis of sensory phenomenon to draw upon.

Vestibular migraine is a clinical syndrome of the central nervous system that is characterized by episodic vestibular symptoms and a history of migraines. It affects approximately 1% of the population [1] and is one of the most common diagnoses in children presenting with vertigo [2].

Around 10 % of the global adult population has active migraine. The public health burden of migraine is high because migraine attacks are associated with temporary disability and substantial impairment in activities. As such, migraine is ranked as one of the most disabling conditions. The widespread disability produced by migraine is therefore an important target for treatment.

The hallmark of migraine is the head pain, but a plethora of other clinical symptoms is needed for a headache to be qualified as a migraine according to the current diagnostic criteria.

There has been tremendous progress in our acceptance, understanding and treatment possibilities of migraine, but to optimize migraine management, it is important that we continue to improve our understanding of the basic migraine mechanisms. An understanding of migraine pathophysiology must encompass the varied clinical symptoms and relate these findings to anatomy and physiology.

Vestibular migraine (VM) describes the condition of episodic vertigo occurring in patients with a history of migraine or other clinical manifestations of migraine. Other terms that have been used nearly interchangeably with vestibular migraine include migrainous vertigo, migraine-associated vertigo, migraine-related vestibulopathy, benign recurrent vertigo, and benign paroxysmal vertigo of childhood.

The headache research field is privileged to have in its preclinical laboratories well-established animal models that significantly facilitate and improve our understanding of headache mechanisms, in particular in terms of the molecular signalling and brain networks involved. A variety of pharmacological screening approaches for novel therapeutics and for the improvement of advanced pharmacological agents can be achieved in translational research utilising these models. The available migraine models have been developed based on our understanding of migraine from clinical, migraine patient-specific evidence. These clinical phenotypes have been successfully employed to model features of the disease physiology in animals and to provide reproducible meaningful physiological measures in the laboratory.

Multiple observational studies have identified a link between patent foramen ovale (PFO) and migraine headache. PFO is found in 40 to 60 % of people who have migraine with aura compared to 20 to 30 % in the general adult population. It is hypothesized that migraine, especially migraine with aura or other transient neurologic deficits, may be triggered by chemicals that are ordinarily metabolized during passage through the lungs. However, the presence of a right-to-left shunt allows these chemicals to bypass metabolic alteration in the lungs and gain entry to the arterial circulation in a higher concentration so that upon reaching the brain, they stimulate receptors in susceptible individuals which produces the cerebral migraine phenomena. This hypothesis was derived after observations that PFO closure for other reasons, such as decompression sickness in divers or to prevent cryptogenic stroke, resulted in relief of migraine headaches. Although migraine is not currently an indication for PFO closure, the possible benefit of percutaneous PFO closure as a treatment for migraine headache will be revealed as results from further prospective randomized trials become available.

Chronic migraine (CM) has complex pathophysiology that cannot be easily studied in humans. Therefore, animal models are ideally suited for this type of investigation and have played crucial roles in our understanding of CM pathophysiology and aid in treatment. Multidisciplinary approaches used in animal models explore anatomical circuits, phenotypic traits, electrophysiological activities, biochemical pathways, and genetic manipulations. Examination of pathophysiology, therapeutic and prophylactic treatment options, drug effects, and non-pharmacological therapies is explored in preclinical settings and helps improve their applications in clinical practice. On the other hand, known CM therapies also benefit from animal models when unraveling drug mechanisms, sensitivity, and toxicity. Thus, even with known limitations, animal models are unraveling CM mechanisms and contributing to the development of therapeutic tools with translational implications that will guide personalized therapies.

Among all chronic daily headache (CDH) disorders, chronic migraine (CM) and chronic tension-type headache (CTTH) contribute to most cases of CDH, followed by new daily persistent headache (NDPH), medication oversue headache (MOH), and hemicrania continua. The most studied CDH type in animal models is CM. We will focus on animal models of CM in this chapter.